Download Relationship of carbon dioxide tension in arterial blood to pulmonary

Copyright #ERS Journals Ltd 2002
European Respiratory Journal
ISSN 0903-1936
Eur Respir J 2002; 19: 37–40
DOI: 10.1183/09031936.02.00214502
Printed in UK – all rights reserved
Relationship of carbon dioxide tension in arterial blood to
pulmonary wedge pressure in heart failure
G. Lorenzi-Filho*, E.R. Azevedo#, J.D. Parker#, T.D. Bradley*
Relationship of carbon dioxide tension in arterial blood to pulmonary wedge pressure in
heart failure. G. Lorenzi-Filho, E.R. Azevedo, J.D. Parker, T.D. Bradley. #ERS
Journals Ltd 2002.
ABSTRACT: Hypocapnia contributes to the genesis of Cheyne-Stokes respiration and
central sleep apnoea in patients with congestive heart failure (CHF) and is associated
with increased mortality. However, the cause of hypocapnia in patients with chronic
stable CHF is unknown. Since pulmonary congestion can induce hyperventilation via
stimulation of pulmonary vagal afferents, the present study tested the hypothesis that in
patients with CHF (carbon dioxide tension in arterial blood (Pa,CO2)) is inversely
related to pulmonary capillary wedge pressure (PCWP), and that alterations in PCWP
would cause inverse changes in Pa,CO2.
In 11 CHF patients undergoing diagnostic cardiac catheterization, haemodynamic
variables and arterial blood gas tensions were measured simultaneously at baseline. In
three patients, these measurements were repeated after coronary angiographic dye
infusion and nitroglycerine infusion.
At baseline, Pa,CO2 correlated inversely with PCWP (r=-0.80, p=0.003). In the three
patients in whom multiple measurements were made, acute alterations in PCWP caused
inversely proportional changes in Pa,CO2.
The present study concludes that in patients with congestive heart failure, pulmonary
capillary wedge pressure is an important determinant of carbon dioxide tension in
arterial blood. These findings imply that hypocapnia in patients with chronic stable
congestive heart failure is a respiratory manifestation of elevated left ventricular filling
pressures.
Eur Respir J 2002; 19: 37–40.
In patients with congestive heart failure (CHF),
hypocapnia (i.e. carbon dioxide tension in arterial
blood (Pa,CO2) v40 mmHg) predisposes to ventilatory
instability and leads to central apnoeas during sleep
when Pa,CO2 falls below the threshold for apnoea [1, 2].
Indeed, CHF patients with Cheyne-Stokes respiration and central sleep apnoea (CSR-CSA) have lower
Pa,CO2 both awake and asleep, than CHF patients
without CSR-CSA [1]. The presence of CSR-CSA
in patients with CHF is associated with increased
mortality probably due to apnoea-related hypoxia,
arousals from sleep and activation of the sympathetic
nervous system [3, 4]. In addition, hypocapnia in
patients with CHF is associated with an increased
prevalence of ventricular arrhythmias [5], which also
predisposes to sudden death. Despite these pathophysiological associations, however, the cause of
hypocapnia in CHF remains to be elucidated.
In animals, increased pulmonary venous pressure induces hyperventilation through stimulation of
pulmonary vagal afferents [6]. Therefore, one possible explanation for hypocapnia in CHF patients is
Depts of Medicine of the *Toronto
General and #Mount Sinai Hospitals/
University Health Network, University
of Toronto, Toronto, Ontario, Canada.
Correspondence: T.D. Bradley, NU 9112 Toronto General Hospital/UHN,
200 Elizabeth Street, Toronto, ON,
M5G 2C4, Canada.
Fax: 416 3404197
Keywords: Arterial blood gas tensions
cardiopulmonary interactions
hypocapnia
Received: February 12 2001
Accepted after revision July 25 2001
The present study was supported by
grants from the Canadian Institutes of
Health Research (MOP-11607) and
from the Heart and Stroke Foundation
of Ontario. G. Lorenzi-Filho was supported by research fellowships from
Fundacao de Amparo a Pesquisa do
Estado de Sao Paulo, Brazil and the
Dept of Medicine of the University of
Toronto. E.R. Azevedo held a research
fellowship from Astra Zeneca/Heart
and Stroke Foundation of Canada.
T.D. Bradley is a Senior Scientist of
the Canadian Institutes of Health
Research.
that stimulation of pulmonary vagal afferents by
high cardiac filling pressures or pulmonary congestion induces hyperventilation. However, only indirect
evidence supports this possibility. For example, it
has been shown that CHF patients with elevated
pulmonary capillary wedge pressure (PCWP) have a
significantly lower Pa,CO2 than patients whose PCWP
is normal [7]. Since oxygen tension in arterial blood
(Pa,O2) is usually normal in such patients, hypoxia
is not likely the cause of hypocapnia [1, 2, 7]. Based
on these observations, it was hypothesized that in
patients with chronic stable CHF, Pa,CO2 would be
inversely related to PCWP and that alterations in
PCWP would cause inverse changes in Pa,CO2.
Methods
Subjects
The subjects were 11 consecutive males aged
between 55–70 yrs who were referred to the Heart
38
G. LORENZI-FILHO ET AL.
Protocol
The protocol was approved by the institutional
ethics committee and written informed consent was
obtained from all patients. Diagnostic right and
left heart catheterization, with patients awake and
without sedation, was performed from the femoral
approach. Right-sided heart catheterization was performed using a flotation catheter positioned in the
right pulmonary artery. Prior to angiography, baseline measurements of pulmonary artery pressure,
mean PCWP, and mean right atrial pressure were
made using a water filled pressure transducer, and
cardiac output was measured by the Fick method. An
arterial blood sample was drawn simultaneously
from the femoral arterial line for analysis of blood
gas tensions. In the last three patients simultaneous
measurements of PCWP and arterial blood gas tensions were made immediately after angiographic dye
infusion, which caused an increase in PCWP, and
during nitroglycerine infusion once PCWP had fallen
by at least 15%. Nitroglycerine was infused at a rate
of 0.8–1.0 mg?kg?min-1. Throughout the procedures,
patients breathed regularly.
Statistical analysis
To assess the potential relationships between Pa,CO2
and a number of physiologically plausible determinants, a multiple stepwise linear regression analysis
was carried out using Pa,O2 alveolar-arterial Pa,O2
gradient, PCWP, right atrial pressure, mean arterial
blood pressure and cardiac index as independent
variables. A backward stepwise regression analysis
was then performed to determine which of these
variables was independently related to Pa,CO2. Among
the three patients in whom multiple arterial blood gas
analyses were performed, repeated measures analysis
of variance (ANOVA) was performed to determine
whether altering PCWP caused any change in Pa,CO2
and other variables. Changes in Pa,CO2 were then
plotted against changes in PCWP. A p-value v0.05
was considered statistically significant.
Table 1. – Baseline characteristics of patients
Characteristics
Baseline characteristics of the patients are shown
in table 1. There were significant correlations between
56¡10
27.9¡6.4
21¡9
87¡17
80¡12
10¡4
20¡5
19¡0.3
7.43¡0.06
79¡18
38¡3
26¡3
Data are presented as mean¡SD; BMI: body mass index;
LVEF: left ventricular ejection fraction; MAP: mean arterial
pressure; RAP: right atrial pressure; PCWP: pulmonary
capillary wedge pressure; CI: cardiac index; bpm: beats per
minute; Pa,O2: oxygen tension in arterial blood; Pa,CO2: carbon dioxide tension in arterial blood; HCO3-: bicarbonate.
Pa,CO2 and PCWP (r=-0.80, p=0.003) (fig. 1), cardiac
index (r=-0.71, p=0.004) and right atrial pressure
(r=-0.76, p=0.008). However, even though two patients
were mildly hypoxic (Pa,O2 of 58 and 54 mmHg) there
were no significant correlations of Pa,CO2 with either
Pa,O2 (r=0.14, p=0.673) or alveolar-arterial partial
pressure of O2 (PO2), gradient (r=-0.33, p=0.325).
Stepwise and backward linear regressions showed that
PCWP was the only variable that correlated significantly and independently with Pa,CO2. Following
dye infusions, PCWP increased (from 18.7 to 21.2,
from 20.4 to 28.5 and from 29.0 to 34.0 mmHg in
the three subjects, respectively). During nitroglycerine
infusions, PCWP consistently decreased (17.2, 18.0
and 18.0 mmHg, respectively). Pa,CO2 changed significantly in response to dye and nitroglycerine
infusions (mean¡SD, 39.7¡2.1 mmHg at baseline, to
36.3¡0.6 mmHg following dye, to 39.3¡1.2 mmHg
during nitroglycerine infusions, p=0.03, dye infusion
different from the others). Pa,O2 were 72¡16, 81¡14
44
42
40
38
36
34
32
12
Results
All patients
Age, yrs
BMI, Kg?m-2
LVEF %
MAP mmHg
Heart rate bpm
RAP mmHg
PCWP mmHg
CI, L/min/m2
pH
Pa,O2 mmHg
Pa,CO2, mmHg
HCO3-, mmol?L-1
Pa,CO2 mmHg
Failure Clinic of the Mount Sinai Hospital, Toronto
for diagnostic assessment of CHF, and who were
undergoing diagnostic cardiac catheterization. Entry
criteria included a left ventricle ejection fraction at rest
of v35% measured by radionuclide angiography. One
patient was in New York Heart Association functional class II and 10 were in class III. The aetiology
of CHF was ischaemic in eight and idiopathic dilated
cardiomyopathy in three patients. Medical therapy
included diuretics in all 11 patients, angiotensinconverting enzyme inhibitors in eight, hydralazine in
one, digoxin in six, and amiodarone in two. Patients
with a history of respiratory disease were excluded.
14
16
18
20
22
24
26
28
30
PCWP mmHg
Fig. 1. – Relationship between carbon dioxide tension in arterial
blood (Pa,CO2) and pulmonary capillary wedge pressure (PCWP)
for all 11 patients. r=0.80; p=0.003.
PA,CO2 AND WEDGE PRESSURE IN HEART FAILURE
Change in Pa,CO2 mmHg
6
4
Nitroglycerine infusion
Dye infusion
●
2
▲
0
-2
▲
●
-4
-6
-20 -15
-10
-5
0
5
10
15
30
Change in PCWP mmHg
Fig. 2. – Acute changes in carbon dioxide tension in arterial blood
(Pa,CO2) as a function of acute variations in pulmonary capillary
wedge pressure (PCWP) due to dye and nitroglycerine infusion in
three patients. Data from the three patients are represented by the
three different symbols.
and 71¡18 mmHg at baseline, after dye and during nitroglycerine infusions, respectively (p=0.13).
Alveolar-arterial PO2 gradients were 38¡17, 33¡14
and 39¡19 mmHg at baseline, after dye and during
nitroglycerine infusions, respectively (p=0.42).
There was a consistent inverse relationship between
changes in Pa,CO2 and changes in PCWP in response
to dye and nitroglycerine infusions (fig. 2). Mean
arterial blood pressures did not change significantly
during the experiment (94¡29 at baseline, to 102¡23
after dye infusion and to 87¡11 mmHg during nitroglycerine infusion respectively, p=0.17).
Discussion
This study is the first in humans with CHF to
demonstrate that PCWP is an independent determinant of Pa,CO2. Evidence for this was provided by two
novel observations. First, among all study subjects,
there was a strong inverse relationship between Pa,CO2
and PCWP. Second, when PCWP was raised by
contrast dye infusion, Pa,CO2 decreased. Conversely,
when PCWP was reduced by nitroglycerine infusion,
Pa,CO2 increased. Changes in Pa,CO2 were inversely
proportional to changes in PCWP. These data
indicate that elevated left ventricular filling pressure
contributes to hypocapnia in patients with CHF.
Hypocapnia plays a key role in the genesis of central apnoeas during CSR-CSA [1]. Central apnoeas
during CSR-CSA are triggered by abrupt increases
in ventilation and falls in Pa,CO2below the threshold for apnoea, which are abolished when Pa,CO2 is
raised by inhalation of a CO2 containing gas mixture during sleep [2]. Hypocapnia and CSR-CSA also
have adverse clinical implications in patients with
CHF. They are associated with increased sympathetic
nervous system activity [8], left ventricular volume [9],
ventricular ectopy [5] and mortality [3, 4].
What causes hyperventilation in CHF? Hypoxia is
39
one possibility. However, studies have consistently
shown that hypocapnia in CHF patients with CSRCSA is not related to hypoxia during normal breathing [1, 5]. The present findings agree with those
observations: Pa,O2 was within normal limits in all
except two patients, and Pa,CO2 bore no significant
relationship to Pa,O2. In patients with CSR-CSA, hypoxia resulting from central apnoeas could lead to respiratory instability through stimulation of ventilation
and consequent reductions in Pa,CO2. However, it was
demonstrated in the present study that inhalation of
supplemental O2 sufficient to abolish apnoea-related
hypoxia had no impact on either Pa,CO2 or on the
frequency of central apnoeas [2]. Taken together, the
above observations strongly suggest that in most
patients with chronic stable CHF, hypoxia is unlikely
to play an important role in causing hypocapnia.
Increased chemosensitivity is another possible cause
of hypocapnia in CHF. JAVAHERI [10] found that
CHF patients with CSR-CSA had increased central
chemosensitivity to CO2 compared to CHF patients
without CSR-CSA. In addition, SOLIN et al. [11] found
both increased central and peripheral sensitivity to
CO2 in CHF patients with CSR-CSA. Furthermore,
experimentally induced CHF has been shown to
increase peripheral chemosensitivity [12]. These findings indicated that the state of cardiac failure itself
can alter respiratory chemosensitivity. However, none
of these studies examined the potential relationship
between Pa,CO2 and chemosensitivity, and between
chemosensitivity and PCWP. Thus, it remains unclear
whether increased chemosensitivity per se is a cause of
hypocapnia in CHF.
Another possible explanation for hypocapnia in
CHF is stimulation of pulmonary vagal irritant
receptors by pulmonary congestion. In animals, high
pulmonary venous pressures induce tachypnoea,
through stimulation of pulmonary vagal afferents
[6]. However, the relationship between pulmonary
venous pressure and Pa,CO2 was not examined. In
humans with CHF, SOLIN et al. [13] found a weak
but significant inverse relationship between Pa,CO2
and PCWP (r=-0.4). However, measurements of
PCWP and Pa,CO2 were performed several days to
weeks apart, and no attempt was made to determine
the effect of altering PCWP on Pa,CO2. Consequently,
they did not establish whether PCWP is an independent determinant of Pa,CO2.
The demonstration of a significant inverse relationship between Pa,CO2 and PCWP in patients with
CHF in the present study, support the findings of
SOLIN et al. [13]. However, in the present study the
findings of SOLIN et al. [13] are extended in several
important ways. Firstly, haemodynamic measurements and arterial blood gas analyses were performed
simultaneously. This probably accounts for the much
stronger relationship between Pa,CO2 and PCWP that
was observed compared to SOLIN et al. [13]. Second, in
contrast to SOLIN et al. [13], other potential influences
on Pa,CO2 were controlled, including cardiac output,
right atrial pressure and Pa,O2. Most importantly,
however, the acute effects of altering PCWP on Pa,CO2
were examined, demonstrating that PCWP contributes to variations in Pa,CO2 independently of other
40
G. LORENZI-FILHO ET AL.
potentially confounding variables, and that acute
changes in PCWP caused proportional inverse
changes in Pa,CO2. The demonstration that Pa,CO2
varied as a function of PCWP supported a cause-effect
relationship between these two variables. However,
data on the effects of altering PCWP on Pa,CO2 were
obtained from only three subjects. This is because the
local ethics review committee provided permission
to infuse nitroglycerine to lower PCWP in only three
subjects owing to the invasiveness and prolonged
nature of the protocols they were undergoing
(discussed later).
In order to determine what factors are associated
with hypocapnia, the present authors had to include
data from subjects with a wide range of Pa,CO2
including some who were normocapnic. In previous
studies, the present authors showed that CHF patients
with CSR-CSA have lower Pa,CO2 than subjects
without CSR-CSA, but that there is some overlap
[1, 14]. In general, patients with CSR-CSA have all
awake Pa,CO2 or v40 mmHg. Therefore, if hypocapnia is considered to be a Pa,CO2 of v40 mmHg, then
six of the present patients were hypocapnic. More
importantly, data from subjects with a lower Pa,CO2
of v40 mmHg fall on the regression line in figure 1.
Alterations in PCWP must have influenced Pa,CO2
through the effect of left ventricular filling pressure
and pulmonary venous pressure on respiratory pattern. Indeed, CHURCHILL and COPE [6] showed that
alterations in pulmonary venous pressure in dogs
caused tachypnoea. However, in the present study it
was not possible to assess respiratory rate and tidal
volume during cardiac catheterization studies. This is
because the protocol for the present study was carried
out on patients who were undergoing another complex study lasting 3–4 h during which right and left
heart catheters, a coronary artery sinus catheter and
an intravenous infusion line were in place. Because of
the extensive instrumentation, and the prolonged
nature of the studies, it was not possible to apply
additional instrumentation to measure respiratory
pattern.
In summary, the results presented here demonstrate
that elevated left ventricular filling pressure is a determinant of hypocapnia in patients with congestive
heart failure. The results also indicate that alterations
in pulmonary capillary wedge pressure cause inverse
changes in the carbon dioxide tension in arterial
blood. This cause-effect relationship is probably
mediated through stimulation of pulmonary vagal
irritant receptors by pulmonary venous congestion [6].
Further experiments will be required to test this
hypothesis. Since hypocapnia plays a critical role in
the genesis of central apnoeas in Cheyne-Stokes
respiration and central sleep apnoea, one important
implication of the present findings is that hypocapnia
and Cheyne-Stokes respiration and central sleep
apnoea are respiratory manifestations of high left
ventricular filling pressures and pulmonary venous
congestion in patients with congestive heart failure.
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